The neuroendocrine stress response is a double-edged sword. Activation of glucocorticoid secretion is clearly essential for adaptation to stressful environmental or physiologic stimuli. However, stress or disease-induced glucocorticoid hypersecretion has serious deleterious consequences on metabolism, cardiovascular tone, immunity and behavior. Thus, it is critical for the organism to carefully limit the strength and duration of neuroendocrine stress activation. In recent years, it has become apparent that a sizable proportion of such stress regulation is mediated by the hippocampal formation of the brain. Integrity of the hippocampus is essential for appropriate inhibition of the stress response. Further, neuroendocrine disturbances are accompanied by hippocampal pathology in numerous stress-related disease processes, including major depression. On the basis of the available data, we have developed the hypothesis that the hippocampus serves to protect the organism from the deleterious consequences of stress by interpreting the significance of incoming stimuli with respect to previous experiences. The aims of the present proposal are designed to test this general hypothesis, and to identify specific neurocircuitry subserving translation of hippocampal information processing into inhibition of neuroendocrine stress responses. Specific Aim l tests the hypothesis that the hippocampus preferentially affects neuroendocrine responses to cognitive stimuli (novelty, conditioning) but not systemic challenge (respiratory distress, immune stimulation). Specific Aim 2 is designed to delineate neurocircuitry subserving hippocampal neuroendocrine modulation, focusing on the hypothesis that activation of the hippocampus by cognitive (but not systemic stress) is translated into inhibition of the stress axis by way of intermediary cell groups proximal to hypothalamic stress-integrative neurons. Specific Aim 3 builds on this circuit analysis by testing the hypothesis that excitatory neurotransmission in subcortical targets of hippocampal outflow leads to inhibition of hypothalamic stress outflow. Together, these studies are expected to define the raphe of the hippocampus in stress processing, and indicate that dysfunction of this structure is a likely mitigating factor in depressive disorder and stress-related disease processes.